A mutation in a protein critical to hearing mimics an inherited human hearing disorder

Biologists have mimicked the mechanism of a human form of deafness in fruit flies by mutating the gene for a key protein involved. They said their findings will offer clues to how this protein, called myosin VIIA, functions in the mechanism that converts sound into nerve impulses. First author on the paper was Sokol Todi in Eberl's laboratory, and the other co-author was Josef Franke in Kiehart's laboratory. Their work was supported by the American Heart Association and the National Institutes of Health.

The researchers were seeking to understand the role of myosin VIIA, which had been found to be defective in the inherited human disorder Usher type1B syndrome, the most common form of combined blindness and deafness in humans. Mutation of the myosin VIIA gene in Usher syndrome results in an impaired ability of the auditory nerves to transmit sensory input to the brain, accompanied by retinitis pigmentosa, a disorder that causes progressive vision loss.

According to Kiehart, while the origin of the disease had been traced in humans, and researchers had produced versions of the disorder by genetically altering mice, much remains unknown about how the defective myosin protein interferes with hearing.

'This protein is found in both humans and the fruit fly Drosophila, and a major question was whether it is used in the same way in both species, even though they have very different hearing mechanisms.' Both flies and humans, however, detect sound through the vibration of receptor cells in their hearing systems, said Kiehart, and myosin VIIA is involved in both.

The researchers studied mutant versions of the fruit fly called 'crinkled,' provided by Franke and Kiehart. The crinkled mutant lacks a functioning gene for myosin VIIA in the hearing system. In their experiments, Eberl and Todi tested whether this defect affected the flies' hearing.

They played the mutant flies a component of the male fly courtship song, as well as pure tones. They found that the nerve cells connected to the flies' auditory structures called scolopidia, did not produce neural electrical signals in response to the sounds, demonstrating that the flies were deaf due to the nonfunctioning protein.

According to Kiehart, detailed studies of the scolopidia structure of the mutant flies revealed aberrations in a structure called a 'dendritic cap,' which covers the end of the scolopidia. This cap connects the scolopidia to the neurons that transmit auditory signals to the brain.

'So, in a way we don't understand, myosin VII actually mediates that attachment but that's the next frontier in this research,' said Kiehart. 'Now, we need to figure out what the myosin is doing to mediate that attachment.'

In their latest studies, the scientists ruled out some possibilities, that mutant myosin VIIA caused defects in junctions between cells in the hearing organ or in transporting certain hearing-related proteins. 'So, we have tried some of the more obvious possibilities, and they don't seem to explain the defect,' said Kiehart. 'So it's going to be a more subtle effect.' Kiehart said that the new studies showed the value of the fruit fly as an animal model for studying the defective protein.

'We can use unique genetic strategies in the fruit fly to understand the machinery of this disorder in a way that can't be done in other animals,' he said. Such strategies involve using genetic methods to selectively suppress or enhance the function of many genes, to discover those that function along with myosin VIIA in hearing. From that understanding, the researchers can deduce the mechanism by which myosin VIIA works.

Also, said Kiehart, since the fly uses the same myosin VIIA protein for different purposes throughout its body, study of those other functions could yield insight into the protein's role in hearing. Such studies will likely yield insights into the mechanism of hearing loss in humans due to the defective gene, he said.

'If we can establish how this myosin functions in flies, what it binds to and what its role is in establishing the structure, we will gain insights into the mammalian system,' he said. 'While we know that the two types of hearing structures are different in detail, like two differently patterned brick walls, we do know that they each use the same basic mortar or the same basic brick.'